Preserving tissue viability and performance following acute ischemia/reperfusion (I/R) would be best accomplished by simultaneously reducing the inflammatory response and enhancing cardiomyocyte resilience. Scores of cellular signaling molecules have been demonstrated to modulate exclusive elements of each of these wound healing processes but none have yet proven to oversee multiple facets concurrently. The EphrinA ligands and their cognate EphA receptors are part of the largest family of typically membrane-bound receptor tyrosine kinases (RTKs). They are differentially expressed in a variety of cells and activation or silencing of bi-directional signaling cascades can influences cel motility and/or adhesive/repulsive behavior. In the heart, we have observed that the ephrinA1 ligand, originally thought to be solely an angiogenic peptide and the only one of the 5 members of the A subclass that can bind to all EphA1-8 receptors, is expressed in murine cardiomyocytes. Our preliminary data indicate that exogenous ephrinA1-Fc administration at the time of coronary artery occlusion preserves cardiac function following I/R injury. Our preliminary data also implicate STAT3 as a signaling intermediate and further, regional differences in EphA-R expression relative to the site of injury may be accountable. More in depth investigation of the mechanisms by which these protective effects occur in vitro and in vivo will be valuable in evaluating the role of ephrinA1/EphA receptors and potential therapeutic value of ephrinA1-Fc in modulating these processes. Specifically, in vitro experiments using isolated adult cardiomyocytes +/- leukocytes pretreated with chimeric ephrinA1-Fc prior to hypoxia and reperfusion will enable comprehensive examination of the signaling mechanisms involved in reducing cardiomyocyte damage. In vivo, comparison of the composition and cell-specific expression characteristics in the infarct margin from the ligation site toward the apex in ephrinA1-Fc treated hearts versus controls will shed light on the mechanisms on protection. Information gleaned from these studies will provide the framework from which to extrapolate the potential capacity of selectively modulating ephrinA1 and EphA receptors to reduce myocardial injury and will be applicable to other ischemic diseases, regenerative medicine, and tissue engineering applications.